A fundamental question in biology is how natural selection shapes the genetic variation responsible for metabolic variation among individuals. Several decades ago it became apparent that many metabolic enzymes are segregating for molecular variation in many organisms including humans. The long range goals of the study proposed will examine the extent to which metabolic variation is associated with molecular variation in the enzymes of universal central metabolic pathways. It will study these mechanisms in the fruit fly Drosophila melanogaster, a model organism for whom the entire genome was sequenced this year. Genetic disorders in metabolism are a major health concern from diabetes to obesity. Many of these disorders have their causes in the genes under investigation. The specific scientific objectives are several. (1) To determine which enzymes, genes and pathways are responding to natural selection. This will involve sequencing a set of genes involved in lipogenesis, glycolysis, gluconeogenesis, the NADH/NAD shuttles, and glutamate metabolism. From patterns of DNA and inferred protein sequence variation and geographic patterns associated with latitude, it will be determined which pathways steps are responding to natural selection to modulate metabolic pools and adapt to ethanol rich niches. (2) To study the functional differences associated with pathway steps seem to be carrying genetic variation associated with patterns of geographic variation. (3) Experimental manipulations will be carried out to evaluate the extent to which individual steps or enzymes can modulate metabolic pools and pathway fluxes. (4) The proximal selective causes associated with latitudinal variation will be investigated. These likely involve selection on delayed senescence in northern regions, as well as associated reallocation of metabolic pools away from reproduction. This will focus on the dichotomous variation of female reproduction diapause and its related phenotypes such as starvation resistance. Studies will begin to identify the genes responsible for the variation in this suite of traits that have cascading effects into the metabolic pathways.